thromboxane-a2 and Bronchitis

The mechanisms of excessive sputum production are only partially understood. We speculated that a selective thromboxane (Tx) A2 synthetase inhibitor, OKY-046, now used in the treatment of asthma in Japan, could decrease excess sputum production in patients with chronic airways disease. To test this hypothesis, we carried out a double-blind, placebo-controlled study of the effects of OKY-046, administered orally at 400 mg.day-1, on the sputum of patients with chronic bronchitis and patients with diffuse panbronchiolitis. Patients treated with OKY-046 showed a significant decrease (22%) in sputum volume after 1 month, and a 39% decrease after 3 months. Although the rheological properties of the sputum and the concentrations of fucose and immunoglobulin (Ig) A in the sputum remained unchanged, significant decreases were observed in the concentrations of total protein, albumin, sialic acid and phospholipid. Since albumin and fucose are chemical markers of plasma exudation and mucus secretion, respectively, whilst sialic acid and phospholipid are derived both from serum and mucus, our results indicate that this TxA2 synthetase inhibitor reduced sputum volume by inhibiting microvascular leakage in the airway. OKY-046 may, therefore, be of value in the treatment of chronic bronchitis and diffuse panbronchiolitis.

Topics: Adult; Aged; Bronchiolitis; Bronchitis; Chronic Disease; Double-Blind Method; Enzyme Inhibitors; Female; Humans; Male; Methacrylates; Middle Aged; Respiratory Function Tests; Rheology; Sputum; Thromboxane A2; Thromboxane-A Synthase

Eicosanoids such as prostaglandin E2 (PGE2), thromboxane A2 (TXA2), and peptidoleukotrienes (pLT) are known to be biologically highly active lipid mediators, especially in human lung epithelium. PGE2 is thought to have mostly bronchoprotective effects, whereas pLT and TXA2 are bronchoconstrictive. This study was undertaken to assess the release and interaction of eicosanoids in human bronchial biopsy specimens of normal and inflamed mucosa.. Bronchial biopsy specimens were obtained from 16 patients, seven controls without signs of inflammation and nine patients with severe inflammatory processes in the epithelium. The release of pLT, TXA2 (measured as TXB2), and PGE2 was investigated using a "functional in vitro test" and the addition of several stimuli.. Specimens incubated with arachidonic acid released higher amounts of pLT, TXB2, and PGE2 than unstimulated specimens. Preincubation with PGE2 revealed significant inhibition of arachidonic acid-induced release of pLT and TXB2 (> 50%). The inhibitory effect was higher in normal than in inflamed epithelium.. Exogenous PGE2 has inhibitory effects on the release of pLT and TXB2 in human bronchial biopsy specimens. This finding could explain the bronchoprotective effect of inhaled PGE2 in normal subjects and asthmatic subjects as direct eicosanoid interactions. It also supports the concept of PGE2 as a bronchoprotective endogenous substance. The complex effects of PGE2 as a modulating mediator in inflammation may be worth investigating.

Topics: Adult; Aged; Arachidonic Acids; Aspirin; Biopsy; Bronchi; Bronchitis; Caffeic Acids; Dinoprostone; Eicosanoids; Humans; Leukotrienes; Middle Aged; Thromboxane A2

A study was made of the effect of ketotifen on the concentration of leukotriene B4, prostacyclin and thromboxane A2 in the liquid of bronchoalveolar lavage and on external respiration and cellular immunity during 4 weeks of the treatment of patients with infection-dependent bronchial asthma and chronic obstructive bronchitis. Inclusion of ketotifen into the treatment of patients with bronchial obstruction exerts a stimulating action on the suppressor component of T-cell immunity, leads to a decrease of the content of leukotriene B4 and thromboxane A2 in the lavage liquid, which is accompanied by positive shifts in the clinical course of the broncho-obstructive syndrome. Ketotifen turned out most effective in patients with an initially low content of the subpopulation of T suppressors and with high concentrations of leukotriene B4 and thromboxane A2 in the liquid of bronchoalveolar lavage.

Topics: Adult; Asthma; Bronchi; Bronchitis; Bronchoalveolar Lavage Fluid; Chronic Disease; Eicosanoids; Epoprostenol; Female; Humans; Ketotifen; Leukotriene B4; Male; Middle Aged; Thromboxane A2

The addition of ketanserin (a blocker of serotonin S2-receptors) to treatment of bronchial obstruction is shown to lower plasma and platelet concentrations of serotonin, leukotriene B4 level in the lavage fluid, to shift prostacyclin-thromboxane balance to the side of prostacyclin. In 40 patients with chronic obstructive bronchitis treated, the above changes were associated with persistent clinical response, a decrease of bronchial obstruction, being the most profound in a group of patients with chronic catarrhal bronchitis.

Topics: Adult; Bronchitis; Bronchoalveolar Lavage Fluid; Chronic Disease; Epoprostenol; Female; Humans; Ketanserin; Leukotriene B4; Male; Middle Aged; Receptors, Serotonin; Respiratory Function Tests; Serotonin; Serotonin Antagonists; Thromboxane A2

A study was made of the content of leukotriene B4, prostacycline and thromboxane A2 in the fluid of bronchoalveolar lavage in 62 patients with chronic bronchitis (CB) in the stage of exacerbation and remission. The time course of changes in the concentration of the eukosanoids was compared with the status of pulmonary local defense factors and cellular immunity. In catarrhal obstructive bronchitis, an important mechanism of a steady maintenance of bronchial obstruction involved a rise of the content of leukotriene B4 whereas in purulent obstructive bronchitis, it was an excess level of thromboxane A2. It is assumed that immunologically dependent activation of the leukotriene B4 and thromboxane synthetase capacity of alveolar macrophages may stipulate the clinical course of CB, modulating the bronchoconstrictor or inflammatory component of the disease. To correct phlogogenous function of alveolar macrophages, the use of immunomodulating therapy with a selective action on the suppressor component of immunity is desirable.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Bronchitis; Bronchoalveolar Lavage Fluid; Bronchoscopy; Chronic Disease; Epoprostenol; Humans; Immunity, Cellular; Leukotriene B4; Middle Aged; Thromboxane A2; Thromboxane B2

To determine whether the involvement of thromboxane A2 in bronchial hyperresponsiveness is specific to asthma, we examined the effects of a selective thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial responsiveness to methacholine in patients with bronchial asthma and chronic bronchitis. The provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20-FEV1) was measured before and after oral administration of OKY-046 and indomethacin in eight asthmatic and 10 bronchitic subjects. Baseline FEV1 value was not altered by OKY-046 or indomethacin. The geometric mean value of PC20-FEV1 increased significantly (p less than 0.005) from 1.78 to 4.27 mg/ml after OKY-046 in asthmatic subjects, but not in bronchitic subjects. On the other hand, PC20-FEV1 was not altered by indomethacin in all subjects. It was concluded that the involvement of thromboxane A2 in bronchial hyperresponsiveness may be specific to asthma.

Topics: Asthma; Bronchi; Bronchial Provocation Tests; Bronchitis; Chronic Disease; Female; Humans; Male; Methacholine Chloride; Methacholine Compounds; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane-A Synthase

To determine whether the involvement of thromboxane A2 in bronchial hyperresponsiveness (BHR) is specific to asthma, we examined the effects of a selective inhibitor of thromboxane synthetase (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial responsiveness to methacholine in normal subjects and patients with chronic bronchitis, diffuse bronchiectasis, and intrinsic bronchial asthma. The provocative concentration of methacholine producing a 20 percent fall in forced expiratory volume in 1 s (PC20-FEV1) was measured before and after oral administration of OKY-046 (2,600 mg over four days) and indomethacin (450 mg over three days) in ten normal, ten bronchitic, nine bronchiectatic, and eight asthmatic subjects, respectively. Baseline values of FEV1 and forced vital capacity (FVC) were not altered by OKY-046 or indomethacin. The geometric mean value of PC20-FEV1 increased significantly (p less than 0.005) from 1.78 to 4.27 mg/ml after OKY-046 in asthmatic subjects, but not in normal, bronchitic, or bronchiectatic subjects. On the other hand, PC20-FEV1 increased significantly (p less than 0.005) from 2.19 to 8.13 mg/ml after indomethacin in bronchiectatic subjects, but not in normal, bronchitic, or asthmatic subjects. We conclude that the involvement of thromboxane A2 in BHR may be specific to asthma, and bronchial responsiveness of bronchiectasis may be potentiated by inflammatory release of bronchoconstrictor prostaglandins except for thromboxane A2. Further studies using thromboxane A2 receptor antagonists are needed to confirm the conclusion.

Topics: Acrylates; Asthma; Bronchi; Bronchial Provocation Tests; Bronchiectasis; Bronchitis; Female; Forced Expiratory Volume; Humans; Indomethacin; Male; Methacholine Chloride; Methacholine Compounds; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane-A Synthase; Vital Capacity